Neuropeptide S receptor (NPSR1) gene variation modulates response inhibition and error monitoring.

The neuropeptide S (NPS) system has been suggested to contribute to the pathogenesis of anxiety. In order to further characterize the cognitive-neurophysiological relevance of neuropeptide S in the etiology of anxiety, the influence of a functional neuropeptide S receptor gene (NPSR1) variant on response inhibition and error monitoring was investigated under consideration of the dimensional phenotype of anxiety sensitivity (AS). In a sample of N=97 healthy probands, event-related potential (ERP) measurement using a modified Flanker task was applied allowing for a distinct neurophysiological examination of processes related to response inhibition (Nogo-N2, Nogo-P3) and error monitoring (Ne/ERN). All subjects were genotyped for the functional NPSR1 A/T (Asn(107)Ile) variant (rs324981) and characterized for anxiety sensitivity using the Anxiety Sensitivity Index (ASI). Carriers of the NPSR1 T allele displayed intensified response inhibition (Nogo-P3) and error monitoring (Ne/ERN), which was in both cases paralleled by the behavioral data. Furthermore, anxiety sensitivity was found to be higher in NPSR1 T allele carriers and to correlate with Nogo-P3 and Ne/ERN. A mediation analysis revealed the ERN to mediate the effect between NPSR1 genotype and anxiety sensitivity. In summary, the more active NPSR1 T allele may confer enhanced response inhibition and increased error monitoring and might drive particularly error monitoring as a neurophysiological endophenotype of anxiety as reflected by increased anxiety sensitivity. These findings further corroborate a major role of the neuropeptide S system in the pathogenesis of anxiety and suggest a potentially beneficial use of therapeutic agents targeting the NPS system in anxiety disorders.

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain.

BACKGROUND: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. METHODOLOGY: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs.Principal findings/resultsIn a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. CONCLUSIONS/SIGNIFICANCE: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.

Understanding the multidimensional phenomenon of medication adherence attitudes in psychosis.

There is an urgent need for a better understanding of the multidimensional factors of medication adherence attitudes in patients with psychosis in order to enhance adherence as up to 75% of patients stop or change their medication within a year. 81 patients with psychosis were assessed on symptom expression, self-stigmatization, adherence attitudes, QoL, social support and therapeutic alliance judged by patients and clinicians. Regression analyses were used to test whether better QoL, more social support and a better therapeutic alliance are associated with more positive and less negative adherence attitudes. More positive clinician input, higher state anxiety and lower levels of self-stigmatization predicted more positive adherence attitudes, while less positive collaboration with the clinician and higher levels of self-stigmatization were associated with more negative adherence attitudes. QoL and social support were unrelated to adherence attitudes. The quality of the therapeutic alliance perceived by patients appears crucial regarding their medication adherence attitudes. Thus, clinicians' focus on psychotic symptom expression is not sufficient to achieve goal agreement. Rather, it is imperative to consider the individual subjective needs of patients as a key element for sustained therapeutic alliance.

The impact of self-stigmatization on medication attitude in schizophrenia patients.

Negative attitudes towards medication in schizophrenia patients are one major factor contributing to non-adherence behavior. Besides, self-stigmatization represents another frequent and important obstacle in patients suffering from psychotic disorders. Here, we investigated possible associations between medication adherence attitude and the extent of self-stigmatization, while also exploring factors related to self-stigmatization. Sociodemographic characteristics, clinical variables, medication attitude and self-stigmatization were assessed among 81 subjects with schizophrenia or schizoaffective disorder. The cross-sectional data was then analyzed by multivariate analyses. A more positive attitude towards medication was predicted by better insight into illness, lower degree of self-stigmatization and good subjective knowledge about medication (adjusted R2 = 0.23). Furthermore, a higher level of self-stigmatization was associated with lower subjective wellbeing, more severe depressive symptoms and male gender (adjusted R2 = 0.58). Other clinical variables had no additional predictive value for medication adherence attitude or the extent of self-stigmatization. Our findings support the notion that self-stigmatization is an influential factor on medication attitude that should therefore be appreciated in clinical practice. Besides this, special emphasis should be taken on depressive symptoms and reduced wellbeing, especially in male patients, to lower the extent of self-stigmatization.

The importance of strengthening competence and control beliefs in patients with psychosis to reduce treatment hindering self-stigmatization.

Different aspects of self-stigmatization represent barriers for recovery in patients with psychosis disorders. It is unclear whether addressing patient's competence and control beliefs could attenuate the extent of self-stigmatization. The major aim of this study was to identify predictors of self-stigmatization derived from competence and control beliefs in patients (N = 80). Sociodemographic characteristics, clinical variables, competence and control beliefs and self-stigmatization were assessed among 80 patients with psychosis disorders. The cross-sectional data was analyzed by correlation and regression analyses. Results indicate deficits in self-concept of own competences, i.e. the capability of acting in new, difficult or ambiguous situations, resulting in also impaired self-efficacy and relatively increased externality in patients compared to a general population sample. Subjective well-being under neuroleptics, trait-anxiety and defining oneself as religious were the most influential predictors of competence and control beliefs. A weaker self-concept of own competences was also revealed as the strongest predictor of overall high self-stigmatization. Our results stress the importance of orienting treatment strategies towards strengthening the self-concept of own competences in patients in order to reduce self-stigmatization and enhance resilience.

Negative impact of self-stigmatization on attitude toward medication adherence in patients with psychosis.

BACKGROUND: Up to 75% of patients suffering from schizophrenia do not take their antipsychotic medication in the way it is prescribed. Nonadherence has been shown to be associated with poorer therapy outcomes, higher hospitalization rates, and increased costs for health care systems. One important contributing factor to negative attitudes toward medication adherence may be self-stigmatization. METHODS: 23 inpatients with a schizophrenia spectrum disorder, all receiving antipsychotic treatment, were assessed for attitude toward medication adherence (using the Rating of Medication Influences [ROMI] scale), subjective well-being under medication (using the Subjective Well-Being under Neuroleptics Scale), and self-stigmatization (using the Internalized Stigma of Mental Illness Inventory). Multiple linear regression analyses were used to predict attitude toward medication adherence from demographic and clinical data and level of self-stigmatization. RESULTS: Patients' gender and their level of self-stigmatization explained 29% of the variance in total attitude toward medication. Inclusion of the self-stigmatization subscore for alienation resulted in an increase of explained variance to 36%. Follow-up analyses of the ROMI pro-adherence subscale scores revealed no correlations with any assessed variables. In contrast, 70% of the variance in the ROMI nonadherence subscale scores was explained by greater alienation, higher number of experienced side effects, less subjective well-being under medication, and female gender. CONCLUSIONS: Our findings imply that reducing the extent of self-stigmatization, especially the feeling of being alienated from society, could improve a negative attitude toward medication adherence in psychosis patients. Cognitive-behavioral therapy offers a variety of therapeutic strategies that could support patients in developing a more positive self-image and in more readily accepting antipsychotic medication as a tool for reaching personal life goals.

Insular and hippocampal gray matter volume reductions in patients with major depressive disorder.

BACKGROUND: Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder. METHODS: For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes. RESULTS: Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala. CONCLUSIONS: The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.

Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia.

OBJECTIVE: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia. METHOD: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores. RESULTS: At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time. CONCLUSIONS: This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated.